Herpes simplex viruses (HSVs) cause a variety of human diseases, including cold sores, eye and genital infections, neonatal infections and encephalitis. The nervous system plays a central role in the pathogenesis of HSV. Both serotypes of the virus, HSV-1 (the oral form) and HSV-2 (the genital form) establish life-long latent infections within sensory ganglia. In addition, the nervous system is the major target of morbidity and mortality resulting from herpetic encephalitis and neonatal herpes. The central role of the neuron in the pathogenesis of HSV argues for experimental approaches that focus on this aspect of HSV infection. This proposal concerns the mechanism by which HSV enter cells of neural origin to initiate infection. Of the eleven virion-encoded glycoproteins, four, including gB, gD and a complex of gH-gL, are essential for virus entry. A fifth, gC though not essential, is important for facilitating initial attachment by binding to cell surface heparan sulfate proteoglycans (HSPG). A major function of gD is to interact with specific cellular receptors. One of these, called herpes virus entry mediator or HVEM, is a member of the tumor necrosis factor receptor (TNFR) superfamily of membrane proteins and is found primarily on T cells and other cells of the immune system. Recently, two additional mediators that allow HSV entry into otherwise non-permissive cells have been identified. Both are orphan receptors with the Ig superfamily of proteins and are homologues of the human polio-virus receptor (hPVR). They have been termed human polio-virus related receptors 1 and 2, or hPRR1 and hPRR2. We found that soluble hPRR1 binds saturably and specifically to soluble forms of gD and to gD in virions No other virion glycoproteins are needed for this interaction. Furthermore, binding of hPRR1 depends on gD conformation but does not involved the N-glycans of gD. Thus, like HVEM, hPRR1 satisfies our expectations for the properties of a bona-fide gD-receptor. We hypothesize that hPRR1 is a major receptor for HSV on cells of neural origin. To test this hypothesis, two specific aims are proposed: 1) to characterize the interaction between purified forms of gD and hPRR1; and 2) to examine the gD-receptor interaction in viruses, cells, and tissues of human neural origin.